The major goal of the project is to elucidate the molecular mechanism underlying diabetes-associated vascular endothelial dysfunction. Diabetes mellitus, one of the major leading chronic morbidities worldwide, is continually increasing with a high prevalence in the United States and throughout the world. Cardiovascular complications are mainly responsible for the high morbidity and mortality in people with diabetes. Vascular endothelial dysfunction in diabetes mellitus critically contributes to the pathogenesis of atherosclerotic disease and its cardiovascular complications. However, the exact molecular mechanisms of endothelial dysfunction in diabetes remain largely unknown. SIRT6, a new member of the sirtuin family of proteins, has recently recognized as a master regulator of stress resistance, gene transcription, genome stability and metabolic homeostasis. SIRT6 has distinct cellular localization and function from other sirtuin family members such as well-studied SIRT1. Recent studies indicate that SIRT6 deficiency is associated with metabolic disease, and SIRT6 has been proposed as a potential therapeutic candidate fighting the metabolic syndrome epidemic. In parallel, emerging evidence from our group suggests that SIRT6 plays a crucial role in regulation of endothelial homeostasis and endothelial SIRT6 deficiency is associated with diabetes. As such we propose that an alternation of SIRT6 expression in diabetes could result in endothelial dysfunction and thus a predisposition to atherosclerosis, and resorting SIRT6 function could improve endothelial homeostasis and protects against atherosclerosis in diabetes. We will use the combination of in vitro and in vivo experiments to test this novel hypothesis. Results from our proposed studies, if as anticipated, would help to understand the molecular basis of endothelial dysfunction, and facilitate the development of new therapeutic approaches, such as enhancing SIRT6 expression and activity, to limit diabetes-accelerated atherosclerotic cardiovascular diseases.